AS349 - Exomic variants and their relation to complex traits in minorities of the WHI (PAGE II)

Investigator Names and Contact Information

Charles Kooperberg (clk@fredhutch.org)

Introduction/Intent

Cardiovascular disease (CVD) is a multifactorial disease with many risk factors including dyslipidemia, hypertension, type 2 diabetes and obesity. These risk factors tend to aggregate in families, but the relative influence of environmental and genetic factors remains unclear. Several studies suggest that CVD risk factors are in part heritable. Recently, genome-wide association studies (GWAS) have identified common risk alleles associated with CVD risk factors. However, in spite of these successes, a significant fraction of the heritability of these traits remains unexplained. The approaches used to date have limited ability to detect rare and less common alleles, and few studies have been conducted in multi-ethnic populations. Furthermore, these approaches may not capture functional variants, hampering investigation of the variants with the most potential for clinical and public health applications. To comprehensively investigate common, less frequent and rare non-synonymous variants across the protein coding regions of the entire genome, the “exome,” and their associations with CVD risk factors we propose to use the newly developed Exomechip genotyping platform in a race/ethnicity diverse subset (n=23,619) of WHI. Newly identified susceptibility loci may better quantify the proportion of CVD risk factor phenotypes explained by genetic variants and also provide insights into CVD molecular pathways.

Specific Aims

A) Identify coding variants associated with cardiovascular disease risk factors (LDL, HDL, triglycerides, creatinine, glucose and insulin concentrations, blood pressure, platelet count, body mass index, and waist-to-hip ratio ) in a well-characterized population of African American, Hispanic and white women with exome data obtained by:

• i. genotyping common [>5% minor allele frequency (MAF)], low frequency (1-5% MAF) and rare (0.1-1% MAF) variants using a redesigned Exomechip which includes the original Exomechip and additional variants selected for minorities for up to 20,000 subjects selected from all WHI African Americans (n=12,151) ,Hispanics (n=5468), Asians (n=3500) and Native Americans (n=600) and a subset of whites (n=6000), and

• ii. using existing exome data from an additional 8000 white WHI participants included in ongoing exome genotyping efforts (4200 colorectal cancer cases and controls) and 4000 bone mineral density participants);

B) Compare race/ethnicity-specific findings across the multiple race/ethnicity groups to confirm and further investigate the most promising variants through collaboration with other cohorts, especially those in the PAGE consortium;

C) Examine whether variants explain a significant proportion of the 'unexplained' heritability for these CVD risk factors, anthroprometric measures, and other intermediate markers; and

D) Examine whether any of the associations identified are modified by environmental factors, such as medication use, dietary factors, physical activity or smoking.